It has been known that meloxicam shows a cyclooxygenase-2-selective anti-inflammatory effect. A non-steroidal anti-inflammatory drug containing meloxicam as an effective component has presently been put on the market as a therapeutic agent for inflammatory diseases and rheumatism, in the form of drugs for internal use and parenteral injections.
It has been reported that if meloxicam is used in the ophthalmic application, it shows a strong anti-inflammatory effect and it also shows a low probability of damaging corneal epithelial cells or the conjunctival cells as compared with the conventional cyclooxygenase-1- and cyclooxygenase-2-nonselective non-steroidal anti-inflammatory agents (International Patent Application Serial No. PCT/JP99/02522).
Moreover, an ophthalmic pharmaceutical preparation containing meloxicam as an effective component is a non-steroidal anti-inflammatory agent and therefore, it would be expected that the pharmaceutical preparation could be used in the treatment of wide variety of diseases such as conjunctivitis, blepharitis, corneitis, scleritis, episcleritis, anterior (ophthalmic) uveitis and post-operative inflammation.
There have been known an ointment, a gel and an eye drop as dosage forms of the ophthalmic pharmaceutical preparation and the eye drop may further be divided into a suspension type pharmaceutical preparation and an aqueous solution type pharmaceutical preparation. The eye drop may easily be administered and therefore, it has widely been used, but the suspension type pharmaceutical preparation suffers from various problems such as uncomfortable feeling with foreign substances (or suspensoids) upon the administration thereof, the scattering of dose and the adhesion of the suspended matter or suspensoids to the container of the suspension. Contrary to this, the aqueous solution type pharmaceutical preparation never suffers from such problems associated with the suspension type one and it is advantageous in that the drug concentration is substantially constant or uniform and that the drug component may easily diffuse upon the administration thereof.
To use a certain drug in the form of an aqueous solution type pharmaceutical preparation (hereunder simply referred to as “aqueous solution”), the drug should be dissolved in water. Therefore, in case where meloxicam is used in the form of an aqueous solution, it is likewise necessary to dissolve A meloxicam in water. However, meloxicam has quite poor solubility in water. More specifically, meloxicam is slightly soluble in an alkaline aqueous solution, but it has a very low solubility in water at an almost neutral pH value.
It has in general been recognized that the pH value of the eye drop preferably ranges from 5 to 9 since it may give a stimulus to the eye (Monthly Ophthalmic Diagnostic Practice, “42. How to Use Eye Drops”, published on Jan. 1, 1999). However, meloxicam could not be dissolved in water at an approximately physiological pH value to a concentration sufficient for ensuring the efficacy thereof.
To use a certain drug in the form of an aqueous solution, not only the drug should be dissolved in water to a concentration sufficient for ensuring the efficacy thereof, but also one should pay close attention to reduce the stimulus to a patient to the lowest possible level since the eye is quite susceptible for stimuli. In addition, the resulting aqueous solution should be excellent in safety and storage stability.
In case where an aqueous solution is prepared using meloxicam as an effective component, the foregoing requirements should likewise be satisfied, but there has not yet been known any conventional report, which can provide any useful suggestion for solving the foregoing problem.
As a method for dissolving meloxicam in water, there has been known a means for forming a salt of meloxicam with meglumine (N-methyl-D-glucamine salt) (Japanese Un-Examined Patent Publication (hereunder referred to as “J.P. KOKAI”) No. Sho 54-92976). However, the meglumine salt of meloxicam suffers from such problems that it has considerably low solubility in water and that if the amount thereof dissolved in water is increased, the pH value of the resulting solution abruptly increases to such an extent that the pH value is beyond the preferred range of from 5 to 9. In fact, the inventors of this invention have tried to prepare an aqueous solution of meloxicam using meglumine, but it has been proved that only a small amount of meloxicam is dissolved in water and the pH value of the resulting aqueous solution is higher than the neutral range or higher than 9.0 and this requires the control of the pH value of the aqueous solution prior to practical use.
In the commercially available injection containing meloxicam, the meloxicam is dissolved using poloxamer as a surfactant and meglumine. This pharmaceutical preparation is excellent in the ability of solubilizing meloxicam as compared with the pharmaceutical preparation in which meloxicam is dissolved simply using meglumine (J.P. KOKAI No. Sho 54-92976), but the former is not preferred from the viewpoint of safety since it comprises a large amount of a surfactant, which may have a probability of causing hemolysis and of damaging cells.
International Publication No. W099/09988 discloses an ophthalmic aqueous gel in which meloxicam is dissolved using β-cyclodextrin. The tissue-transfer ability of the drug, which is dissolved in water through the formation of a clathlate compound with β-cyclodextrin is dependent on the strength of the bond of the drug with the β-cyclodextrin and accordingly, it has been pointed out that the bioavailability of the drug included in the eye drop, which makes use of β-cyclodextrin as a solubilizing agent, is low as compared with the commonly used eye drop. In addition, the gel suffers from a problem such that it is limited in the applications, as compared with the eye drop.
As has been discussed above in detail, it is very difficult to prepare an aqueous pharmaceutical preparation or a solution comprising meloxicam as an effective component, which is less stimulative to a patient and has high safety and excellent storage stability. For this reason, there has not yet been put on the market any ophthalmic aqueous pharmaceutical preparation containing meloxicam as an effective component.